Hepatocyte Growth Factor (HGF) has been identified as a potent mitogen for hepatocytes. HGF was also identified as a secretory protein of fibroblasts and smooth muscle that induces motility of epithelial cells. HGF is also referred to in the literature as Scatter Factor (SF).
HGF is a multifunctional heterodimeric polypeptide produced predominantly by mesenchymal cells, which acts as a ligand for the Met receptor tyrosine kinase (Met). The human Met receptor is also known as “c-met.” Signaling through the Met receptor tyrosine kinase-HGF (Met-HGF) pathway has been shown to lead to an array of cellular responses, including, but not limited to proliferation (mitosis), scattering (motility), stimulation of cell movement through a matrix (invasion), and branching morphogenesis. In vivo, the Met-HGF signaling pathway (Met-HGF) plays a role in, e.g., neural induction, liver regeneration, wound healing, angiogenesis, growth, invasion, morphologic differentiation, and normal embryological development. In addition to these functions, the Met-HGF pair may also play a role in human cancers. Aberrant Met-HGF signaling has been shown to be involved in tumorigenesis, particularly in the development of the invasive and metastatic phenotypes. Certain pathogens, such as malaria, have also been found to exploit aberrant Met-HGF signaling. See Carrolo et al., Nat Med. 2003 9(11):1363-9 (Oct. 12, 2003), the contents of which are hereby incorporated by reference for any purpose.
Further, some groups have reported that HGF may play a role in angiogenesis and in angiogenesis-mediated disease, such as proliferative diabetic reinopathy or macular degeneration. See e.g., Grant, D. S. et al., Proc. Nat. Acad. Sci. U.S.A. 90(5) 1937-41 (1993); Bussolino et al., J. Cell Biol., 119(3):629-641 (1992); Montesano et al., Cell, 67:901-908 (1991); Canon et al., Br. J. Ophthalmol. 84(7):732-5 (2000). HGF may also play a role in apoptosis or programmed cell death. Tumors can arise when normal regulatory mechanisms fail to maintain a balance between proliferation and apoptosis, such that cells accumulate in excess numbers. HGF can effect both proliferation and apoptosis, depending on the biological context.
Because HGF is involved in many physiological processes, in certain instances, it may be useful to have molecules that can regulate its activity. For example, in certain instances, such molecules may be useful for treating a variety of different types of cancer.